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Open Access Publications from the University of California

An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike.

  • Author(s): Schoof, Michael;
  • Faust, Bryan;
  • Saunders, Reuben A;
  • Sangwan, Smriti;
  • Rezelj, Veronica;
  • Hoppe, Nick;
  • Boone, Morgane;
  • Billesbølle, Christian B;
  • Puchades, Cristina;
  • Azumaya, Caleigh M;
  • Kratochvil, Huong T;
  • Zimanyi, Marcell;
  • Deshpande, Ishan;
  • Liang, Jiahao;
  • Dickinson, Sasha;
  • Nguyen, Henry C;
  • Chio, Cynthia M;
  • Merz, Gregory E;
  • Thompson, Michael C;
  • Diwanji, Devan;
  • Schaefer, Kaitlin;
  • Anand, Aditya A;
  • Dobzinski, Niv;
  • Zha, Beth Shoshana;
  • Simoneau, Camille R;
  • Leon, Kristoffer;
  • White, Kris M;
  • Chio, Un Seng;
  • Gupta, Meghna;
  • Jin, Mingliang;
  • Li, Fei;
  • Liu, Yanxin;
  • Zhang, Kaihua;
  • Bulkley, David;
  • Sun, Ming;
  • Smith, Amber M;
  • Rizo, Alexandrea N;
  • Moss, Frank;
  • Brilot, Axel F;
  • Pourmal, Sergei;
  • Trenker, Raphael;
  • Pospiech, Thomas;
  • Gupta, Sayan;
  • Barsi-Rhyne, Benjamin;
  • Belyy, Vladislav;
  • Barile-Hill, Andrew W;
  • Nock, Silke;
  • Liu, Yuwei;
  • Krogan, Nevan J;
  • Ralston, Corie Y;
  • Swaney, Danielle L;
  • García-Sastre, Adolfo;
  • Ott, Melanie;
  • Vignuzzi, Marco;
  • QCRG Structural Biology Consortium;
  • Walter, Peter;
  • Manglik, Aashish
  • et al.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters host cells via an interaction between its Spike protein and the host cell receptor angiotensin-converting enzyme 2 (ACE2). By screening a yeast surface-displayed library of synthetic nanobody sequences, we developed nanobodies that disrupt the interaction between Spike and ACE2. Cryo-electron microscopy (cryo-EM) revealed that one nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains locked into their inaccessible down state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains function after aerosolization, lyophilization, and heat treatment, which enables aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia.

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